U.S. patent number 9,814,673 [Application Number 15/066,731] was granted by the patent office on 2017-11-14 for intraocular lens comprising pharmaceutical compositions and methods for fabricating thereof.
This patent grant is currently assigned to Imprimis Pharmaceuticals, Inc.. The grantee listed for this patent is IMPRIMIS PHARMACEUTICALS, INC.. Invention is credited to Mark L. Baum, Thomas Harvey, Gary Seelhorst.
United States Patent |
9,814,673 |
Seelhorst , et al. |
November 14, 2017 |
Intraocular lens comprising pharmaceutical compositions and methods
for fabricating thereof
Abstract
Medical articles are described, comprising a lens and a
pharmaceutical composition incorporated into the lens, the
compositions consisting essentially of a therapeutically effective
quantity of an anti-bacterial agent (such as moxifloxacin), a
therapeutically effective quantity of an anti-inflammatory agent
(such as prednisolone) and at least one pharmaceutically acceptable
excipient. Methods for fabricating the medical articles and using
them are also described.
Inventors: |
Seelhorst; Gary (San Diego,
CA), Harvey; Thomas (Eau Claire, WI), Baum; Mark L.
(San Diego, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
IMPRIMIS PHARMACEUTICALS, INC. |
San Diego |
CA |
US |
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Assignee: |
Imprimis Pharmaceuticals, Inc.
(San Diego, CA)
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Family
ID: |
56285891 |
Appl.
No.: |
15/066,731 |
Filed: |
March 10, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20160193144 A1 |
Jul 7, 2016 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14458049 |
Aug 12, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/58 (20130101); A61K 47/10 (20130101); A61K
31/4709 (20130101); A61K 9/0019 (20130101); A61K
31/573 (20130101); A61K 9/0051 (20130101); A61K
31/196 (20130101); A61K 38/14 (20130101); A61K
9/0048 (20130101); A61K 38/14 (20130101); A61K
2300/00 (20130101); A61K 31/4709 (20130101); A61K
2300/00 (20130101); A61K 31/573 (20130101); A61K
2300/00 (20130101); A61K 31/196 (20130101); A61K
2300/00 (20130101); A61K 47/26 (20130101); A61K
47/183 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 31/4709 (20060101); A61K
47/10 (20170101); A61K 31/196 (20060101); A61K
31/573 (20060101); A61K 31/58 (20060101); A61K
38/12 (20060101); A61K 38/14 (20060101); A61K
47/26 (20060101); A61K 47/18 (20170101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO2008144347 |
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May 2008 |
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WO |
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(WO2008/144347 |
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Nov 2008 |
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WO |
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2016/024956 |
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Feb 2016 |
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WO |
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Other References
Sharma et al. (Moxifloxacin Loaded Contact Lens for Ocular
Delivery--An In Vitro Study).Jan. 2011. cited by examiner .
Scripture et al. "The Last Hurdle--Taking Cataract Surgery
Dropless," Cataract & Refractive Surgery Today, Jun. 2014, pp.
52-53, Bryn Mawr Communications LLC, Wayne, PA, USA. cited by
applicant .
Da Cunha et al. "Efficacy and Tolerability of a
Gatifloxacin/Prednisolone Acetate Fixed Combination for Topical
Prophylaxis and Control of Inflammation in Phacoemulsification: a
20-Day-Double-Blind Comparison to its Individual Components,"
Clinics, Jun. 2013, 68(6)834-839, FMUSP, Sao Paulo, Brazil. cited
by applicant .
Paganelli et al. "A Single Intraoperative Sub-Tenon's Capsule
Injection of Triamcinolone and Ciprofloxacin in a
Controlled-Release System for Cataract Surgery," Investigative
Ophthalmology & Visual Science--IOVS, Association for Research
in Vision and Ophthalmology, US, Jul. 2009, 50(7)3041-3047, ARVO
Journals, Rockville, MD, USA. cited by applicant .
Cardillo et al. "Subconjunctival Delivery of Antibiotics in a
Controlled-Release System: A Novel Anti-Infective Prophylaxis
Approach for Cataract Surgery," Archives of Ophthalmology, Jan.
2010, 128(1)81-87, AMA Publishing Group, Chicago, IL, USA. cited by
applicant .
Espiritu et al. "Efficacy and Tolerability of a Combined
Moxifloxacin/Dexamethasone Formulation for Topical Prophylaxis in
Phacoemulsification: An Open-Label Single-Arm Clinical Trial,"
Journal of Ophthalmology, 2011, vol. 2011, 5 pgs, Hindawi
Publishing Corporation, New York, NY, USA. cited by applicant .
Lipnitzki et al. "Hydrophilic Acrylic Intraocular Lens as a Drug
Delivery System: Influence of the Presoaking Time and Comparison to
Intracameral Injection," Journal of Ocular Pharmacology and
Therapeutics, 2013, 29(4)414-418, Mary Ann Liebert, Inc.
Publishers, New Rochelle, NY, USA. cited by applicant .
Gonzalez-Chomon et al. "Drug-Eluting Intraocular Lenses,"
Materials, Nov. 2011, 4(11)1927-1940, MDPI AG, Basel, Switzerland.
cited by applicant .
PCT/US2014/050751 International Search Report and Written Opinion
dated Nov. 13, 2014. cited by applicant .
Portoles et al. "Poloxamer 407 as a Bacterial Abhesive for Hydrogel
Contact Lenses," Journal of Biomedical Materials Research, 1994,
28:303-309, John Wiley & Sons, Inc. cited by applicant.
|
Primary Examiner: Blanchard; David J
Assistant Examiner: Alawadi; Sarah
Attorney, Agent or Firm: Wagenknecht IP Law Group PC
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This is a continuation-in-part patent application of U.S. patent
application Ser. No. 14/458,049 filed on Aug. 12, 2014, entitled
"Intraocular Lens Comprising Pharmaceutical Compositions and
Methods for Fabricating Thereof," and claims priority under 35
U.S.C. .sctn.120 to the same, the entire contents of which is
hereby incorporated by reference.
Claims
What is claimed is:
1. A medical article of manufacture, consisting of: (a) an
intraocular lens that is originally free of pharmaceutically active
compounds; and (b) a pharmaceutical composition incorporated into
the lens, wherein the pharmaceutical composition is a suspension
consisting of: (b 1) a dispersed phase consisting of solid
particles consisting of a therapeutically effective quantity of a
corticosteroid and pharmaceutically acceptable salts, hydrates,
solvates, ethers, esters, acetals and ketals thereof; and (b2) a
dispersion medium consisting of: (1) a therapeutically effective
quantity of an anti-bacterial agent independently selected from the
group consisting of quinolone, a fluorinated quinolone and
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof; (2) a therapeutically effective quantity of a
pharmaceutically acceptable solubilizing and suspending agent
selected from the group consisting of non-ionic
polyoxyethlene-polyoxypropylene block copolymers and polysorbates;
(3) a therapeutically effective quantity of a glycopeptide
antibiotic selected from the group consisting of vancomycin,
teicoplanin, telavancin, decaplanin, ramoplanin, gentamicin,
tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and
trimethoprim; (4) a therapeutically effective quantity of a
non-steroid anti-inflammatory drug selected from the group
consisting of bromfenac, ketorolac, etodolac, sulindac, diclofenac,
aceclofenac, nepafenac, tolmetin, indomethacin, nabumetone,
ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexibuprofen,
fenoprofen, loxoprofen, oxaprozin, naproxen, aspirin, salicylic
acid, diflunisal, salsalate, mefenamic acid, meclofenamic acid,
flufenamic acid, tolfenamic acid, meloxicam, piroxicam, ternoxicam,
droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib,
parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide,
clonixin, licofelone, and pharmaceutically acceptable salts,
hydrates, solvates, ethers, esters, acetals and ketals thereof; and
(5) a pharmaceutically acceptable carrier, wherein the dispersed
phase is dispersed within the dispersion medium, and wherein at
least about 99.8% of all the solid particles in the dispersed phase
have a size of 10 .mu.M or less.
2. The medical article of claim 1, wherein the anti-bacterial agent
is a fluorinated quinolone selected from the group consisting of
moxifloxacin and gatifloxacin.
3. The medical article of claim 1, wherein the corticosteroid is
selected from the group consisting of triamcinolone, triamcinolone
acetonide, triamcinolone diacetate, triamcinolone benetonide,
triamcinolone furetonide, triamcinolone hexacetonide, betamethasone
acetate, dexamethasone, fluorometholone, fluocinolone acetonide,
prednisone, prednisolone, methylprednisone, corticol, cortisone,
fluorocortisone, deoxycorticosterone acetate, aldosterone and
budesonide.
4. The medical article of claim 3, wherein the corticosteroid is
selected from the group consisting of triamcinolone, dexamethasone,
prednisone and prednisolone.
5. The medical article of claim 4, wherein the corticosteroid is
triamcinolone.
6. The medical article of claim 1, wherein: (a) the anti-bacterial
agent is moxifloxacin; and (b) the corticosteroid is triamcinolone
or a derivative thereof.
7. The medical article of claim 1, wherein the solubilizing and
suspending agent is selected from the group consisting of non-ionic
polyoxyethylene-polyoxypropylene block copolymers.
8. The medical article of claim 7, wherein the non-ionic
polyoxyethlene-polyoxypropylene block copolymer is poly(ethylene
glycol)-block-poly(propylene glycol)-block-poly(ethylene
glycol).
9. The medical article of claim 1, wherein in the pharmaceutical
composition: (a) the anti-bacterial agent is moxifloxacin at a
concentration of about 1.0 mg/mL; (b) the corticosteroid is
triamcinolone acetonide at a concentration of about 15.0 mg/mL; and
(c) the solubilizing and suspending agent is poly(ethylene
glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) at
a concentration of about 1.0 mass %.
10. The medical article of claim 1, wherein the lens is a
hydrophilic intraocular lens.
11. The medical article of claim 10, wherein the intraocular lens
is fabricated of poly(2-hydroxyethyl methacrylate).
12. A medical article of manufacture, consisting of: (a) an
intraocular lens that is originally free of pharmaceutically active
compounds; and (b) a pharmaceutical composition incorporated into
the lens, wherein the pharmaceutical composition is a suspension
consisting of: (b1) a dispersed phase consisting of solid particles
consisting of a therapeutically effective quantity of a
corticosteroid and pharmaceutically acceptable salts, hydrates,
solvates, ethers, esters, acetals and ketals thereof; and (b2) a
dispersion medium consisting of: (1) a therapeutically effective
quantity of an anti-bacterial agent independently selected from the
group consisting of quinolone, a fluorinated quinolone and
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof; (2) a therapeutically effective quantity of a
pharmaceutically acceptable solubilizing and suspending agent
selected from the group consisting of non-ionic
polyoxyethlene-polyoxypropylene block copolymers and polysorbates;
(3) a therapeutically effective quantity of a glycopeptide
antibiotic selected from the group consisting of vancomycin,
teicoplanin, telavancin, decaplanin, ramoplanin, gentamicin,
tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and
trimethoprim; and (4) a pharmaceutically acceptable carrier,
wherein the dispersed phase is dispersed within the dispersion
medium, and wherein at least about 99.8% of all the solid particles
in the dispersed phase have a size of 10 .mu.M or less.
13. The medical article of claim 12, wherein the anti-bacterial
agent is a fluorinated quinolone selected from the group consisting
of moxifloxacin and gatifloxacin.
14. The medical article of claim 12, wherein the corticosteroid is
selected from the group consisting of triamcinolone, triamcinolone
acetonide, triamcinolone diacetate, triamcinolone benetonide,
triamcinolone furetonide, triamcinolone hexacetonide, betamethasone
acetate, dexamethasone, fluorometholone, fluocinolone acetonide,
prednisone, prednisolone, methylprednisone, corticol, cortisone,
fluorocortisone, deoxycorticosterone acetate, aldosterone and
budesonide.
15. A medical article of manufacture, consisting of: (a) an
intraocular lens that is originally free of pharmaceutically active
compounds; and (b) a pharmaceutical composition incorporated into
the lens, wherein the pharmaceutical composition is a suspension
consisting of: (b1) a dispersed phase consisting of solid particles
consisting of a therapeutically effective quantity of a
corticosteroid and pharmaceutically acceptable salts, hydrates,
solvates, ethers, esters, acetals and ketals thereof; and (b2) a
dispersion medium consisting of: (1) a therapeutically effective
quantity of an anti-bacterial agent independently selected from the
group consisting of quinolone, a fluorinated quinolone and
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof; (2) a therapeutically effective quantity of a
pharmaceutically acceptable solubilizing and suspending agent
selected from the group consisting of non-ionic
polyoxyethlene-polyoxypropylene block copolymers and polysorbates;
(3) a therapeutically effective quantity of a non-steroid
anti-inflammatory drug selected from the group consisting of
bromfenac, ketorolac, etodolac, sulindac, diclofenac, aceclofenac,
nepafenac, tolmetin, indomethacin, nabumetone, ketoprofen,
dexketoprofen, ibuprofen, flurbiprofen, dexibuprofen, fenoprofen,
loxoprofen, oxaprozin, naproxen, aspirin, salicylic acid,
diflunisal, salsalate, mefenamic acid, meclofenamic acid,
flufenamic acid, tolfenamic acid, meloxicam, piroxicam, ternoxicam,
droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib,
parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide,
clonixin, licofelone, and pharmaceutically acceptable salts,
hydrates, solvates, ethers, esters, acetals and ketals thereof; and
(4) a pharmaceutically acceptable carrier, wherein the dispersed
phase is dispersed within the dispersion medium, and wherein at
least about 99.8% of all the solid particles in the dispersed phase
have a size of 10 .mu.M or less.
16. The medical article of claim 15, wherein the anti-bacterial
agent is a fluorinated quinolone selected from the group consisting
of moxifloxacin and gatifloxacin.
17. The medical article of claim 15, wherein the corticosteroid is
selected from the group consisting of triamcinolone, triamcinolone
acetonide, triamcinolone diacetate, triamcinolone benetonide,
triamcinolone furetonide, triamcinolone hexacetonide, betamethasone
acetate, dexamethasone, fluorometholone, fluocinolone acetonide,
prednisone, prednisolone, methylprednisone, corticol, cortisone,
fluorocortisone, deoxycorticosterone acetate, aldosterone and
budesonide.
Description
FIELD OF THE INVENTION
The present invention relates generally to the field of
ophthalmology and more specifically to injectable ophthalmological
compositions having anti-bacterial and anti-inflammatory
properties, and to methods of preparing such compositions.
BACKGROUND
In ophthalmological treatments and procedures, e.g., cataract
surgery, pre- and post-operative eye drops are frequently used by
the patients to eliminate or alleviate negative post-surgery
complications such as infections, inflammation, and tissue edema.
It has been reported that as many as 8% of all ocular surgery
patients may suffer from infections, including the potentially
catastrophic endophthalmitis, and various negative sight
threatening side effects after surgery, such as inflammatory
uveitis, corneal edema, and cystoid macular edema. Typically, the
topical postoperative medications are prescribed for at-home use
starting before and then after cataract surgery, and are typically
self-administered, unless requiring a caregiver or family
assistance.
These ophthalmic medication drops include anti-inflammatory and
antibiotic agents and are highly effective, but require strict
adherence to the treatment regimens, which is often difficult for
many patients (with physical limitations or aversions to eyelid
touching and manipulation) and is frequently expensive (well over
$200 per procedure), causing patients' dissatisfaction. It is
desirable to have an alternative procedure that would permit
avoiding the necessity of the use of such post-surgery medications
to save the associated post-operative trouble and expenses.
One such alternative procedure includes the intraoperative
intravitreal injection by an atraumatic transzonular route that can
achieve patient outcomes that are as good as, or better than, the
current at-home eye drop regimen, removing the issues of compliance
and medication administration accuracy. This patent specification
discloses pharmaceutical compositions suitable for intraoperative
ocular injections that can achieve such positive patient outcomes,
and methods of fabricating and administering the same.
SUMMARY
According to one embodiment of the invention, a pharmaceutical
composition for intraocular injection is provided, the composition
comprising a therapeutic component consisting essentially of a
therapeutically effective quantity of an anti-bacterial agent and a
therapeutically effective quantity of an anti-inflammatory agent,
and at least one pharmaceutically acceptable excipient and/or a
pharmaceutically acceptable carrier that are suitable for
intraocular injection.
According to another embodiment of the invention, an anti-bacterial
agent described herein can be a compound selected from the group of
quinolone (including a fluorinated quinolone), e.g., moxifloxacin,
and pharmaceutically acceptable salts, hydrates, solvates or
N-oxides thereof.
According to yet another embodiment of the invention, an
anti-inflammatory agent described herein can be a corticosteroid,
e.g., triamcinolone, and pharmaceutically acceptable salts,
hydrates, solvates, ethers, esters, acetals and ketals thereof
According to other embodiments of the invention, the pharmaceutical
compositions described herein may be formulated as two-phase
suspensions incorporated into a lens, suspensions consisting of a
dispersed phase consisting of solid particles of corticosteroid(s)
and a dispersion medium in which the dispersed phase is dispersed,
the dispersion medium consisting of anti-bacterial agent(s) (e.g.,
various quinolone(s)), solubilizing and suspending agent(s), such
as non-ionic polyoxyethylene-polyoxypropylene block copolymer(s),
optionally, a therapeutically effective quantity of glycopeptide
antibiotic(s), optionally, a therapeutically effective quantity of
non-steroid anti-inflammatory drug(s), and a pharmaceutically
acceptable carrier.
According to other embodiments of the invention, the pharmaceutical
compositions described herein may be intravitreally transzonularly
injected into a mammalian subject as a part of the process of
treatment of a variety of ophthalmological diseases, conditions or
pathologies associated with intraocular surgery, such as cataracts,
retinal and glaucoma disease.
DETAILED DESCRIPTION
A. Terms and Definitions
Unless specific definitions are provided, the nomenclatures
utilized in connection with, and the laboratory procedures and
techniques of analytical chemistry, synthetic organic and inorganic
chemistry described herein, are those known in the art. Standard
chemical symbols are used interchangeably with the full names
represented by such symbols. Thus, for example, the terms
"hydrogen" and "H" are understood to have identical meaning.
Standard techniques may be used for chemical syntheses, chemical
analyses, formulating compositions and testing them. The foregoing
techniques and procedures can be generally performed according to
conventional methods well known in the art.
It is to be understood that both the foregoing general description
and the following detailed description are exemplary and
explanatory only and are not restrictive of the invention claimed.
As used herein, the use of the singular includes the plural unless
specifically stated otherwise. The section headings used herein are
for organizational purposes only and are not to be construed as
limiting the subject matter described.
As used herein, "or" means "and/or" unless stated otherwise.
Furthermore, use of the term "including" as well as other forms,
such as "includes," and "included," is not limiting.
"About" as used herein means that a number referred to as "about"
comprises the recited number plus or minus 1-10% of that recited
number. For example, "about" 100 degrees can mean 95-105 degrees or
as few as 99-101 degrees depending on the context. Whenever it
appears herein, a numerical range such as "1 to 20" refers to each
integer in the given range; i.e., meaning only 1, only 2, only 3,
etc., up to and including only 20.
The term "pharmaceutical composition" is defined as a chemical or a
biological compound or substance, or a mixture or combination of
two or more such compounds or substances, intended for use in the
medical diagnosis, cure, treatment, or prevention of disease or
pathology.
The term "suspension" is defined for the purposes of the present
application as a two-phase dispersion system having a first phase
and a second phase. It is further specifically provided that
dispersion systems having three, four or more phases are not within
the meaning of "suspension" for the purposes of the instant
application.
Furthermore, the above mentioned first phase of the suspension
consists of a multitude of solid particles and is designated and
defined as the "dispersed phase", and the above mentioned second
phase of the suspension is a liquid and is designated and defined
as the "dispersion medium", or, interchangeably and synonymously,
the "continuous phase".
Furthermore, the above mentioned "dispersed phase" is dispersed in
the above mentioned "dispersion medium", and the term "dispersed"
is defined as meaning that the "dispersed phase" is statistically
evenly distributed throughout the entire volume of the suspension,
with no statistically meaningful deviations in the concentrations
of the dispersed phase in different portions of the suspension.
The term "intraocular injection" refers to an injection that is
administered by entering the eyeball of the patient.
The term "transzonular" refers to an injection administered through
the ciliary zonule which is a series of fibers connecting the
ciliary body and lens of the eye.
The term "intravitreal" refers to an injection administered through
an eye of the patient, directly into the inner cavity of the
eye.
The term "intraoperative" is defined as an action occurring or
carried during, or in the course of, surgery.
The term "intraocular lens" or "IOL" is defined as lens implanted
in the eye used to treat cataracts or myopia, and as used herein,
the IOL is inclusive of both phakic and pseudophakic IOL and is
also inclusive of the IOL fabricated from both hydrophilic and
hydrophobic materials as the terms "hydrophilic" and "hydrophobic"
are understood by those having ordinary skill in the art.
The terms "incorporated" and "ensconced" are used herein to mean
combining two or more separate elements as to form an
indistinguishable whole that cannot be easily separated into the
original constituent part. For instance, when the instant
application recites "incorporating" or "ensconcing" a
pharmaceutical composition into the IOL, it means that once the
pharmaceutical composition is so ensconced, it cannot be physically
separated from the IOL, in a reasonably easy fashion.
The terms "anti-bacterial" and "antibiotic" used herein
interchangeably, refer to substances or compounds that destroy
bacteria and/or inhibit the growth thereof via any mechanism or
route.
The term "anti-inflammatory" refers to substances or compounds that
counteract or suppress inflammation via any mechanism or route.
The terms "non-steroid anti-inflammatory drug" or "NSAID" refer to
substances or compounds that are free of steroid moieties and
provide analgesic, antipyretic and/or anti-inflammatory
effects.
The term "quinolone" for the purposes of this application refers to
a genus of anti-bacterial compounds that are derivatives of
benzopyridine and in some embodiments include fluorine atom, such
as in the following structure ("fluoroquinolone"):
##STR00001##
The terms "corticosteroid" and closely related "glucocorticoid" are
defined as compounds belonging to a sub-genus of steroids that are
derivatives of corticosterone, the latter having the chemical
structure:
##STR00002##
The term "salt" refers to an ionic compound which is a product of
the neutralization reaction of an acid and a base.
The terms "solvate" and "hydrate" are used herein to indicate that
a compound or a substance is physically or chemically associated
with a solvent for "solvates" such as water (for "hydrates").
The term "ether" refers to a chemical compound containing the
structure R--O--R.sub.1, where two organic fragments R and R.sub.1
are connected via oxygen.
The term "ester" refers to a chemical compound containing the ester
group R--O--C(O)--R.sub.1, connecting two organic fragments R and
R.sub.1.
The terms "acetal" and "ketal" refer to a chemical compound
containing the functional group R--C(R.sub.1)(OR.sub.2).sub.2,
where R and R.sub.2 are organic fragments and R.sub.1 is hydrogen
atom (for acetals), and is inclusive of "hemiacetals" where one
R.sub.2 (but not the other) is hydrogen atom; or where none of R,
R.sub.1 and R.sub.2 is a hydrogen atom and each is an organic
fragment (for ketals).
The term "carrier" refers to a substance that serves as a vehicle
for improving the efficiency of delivery and the effectiveness of a
pharmaceutical composition.
The term "excipient" refers to a pharmacologically inactive
substance that is formulated in combination with the
pharmacologically active ingredient of pharmaceutical composition
and is inclusive of bulking agents, fillers, diluents and products
used for facilitating drug absorption or solubility or for other
pharmacokinetic considerations.
The term "therapeutically effective amount" is defined as the
amount of the compound or pharmaceutical composition that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher, medical
doctor or other clinician.
The term "pharmaceutically acceptable" is defined as a carrier,
whether diluent or excipient, that is compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
The terms "administration of a composition" or "administering a
composition" is defined to include an act of providing a compound
of the invention or pharmaceutical composition to the subject in
need of treatment.
B. Embodiments of the Invention
According to embodiments of the present invention, pharmaceutical
compositions intended to prevent and/or treat inflammation and/or
infections are provided. The compositions include an active
component comprising, consisting essentially of, or consisting of a
therapeutically effective quantity of an anti-bacterial agent
(i.e., an antibiotic) and a therapeutically effective quantity of
an anti-inflammatory agent (e.g., a corticosteroid). In some
embodiments, the pharmaceutical compositions can be used for
intraocular injections. In other embodiments the pharmaceutical
compositions can be used for intra-articular or intra-lesional use.
The compositions further include one or several pharmaceutically
acceptable excipient(s) and one or several pharmaceutically
acceptable carrier(s).
The concentration of the anti-bacterial agent in the pharmaceutical
composition may be between about 0.01 mg/mL and about 50.0 mg/mL,
such as between about 0.5 mg/mL and about 10 mg/mL, for example,
about 1.0 mg/mL. The concentration of the anti-inflammatory agent
in the pharmaceutical composition may be between about 0.1 mg/mL
and about 100.0 mg/mL, such as between about 5.0 mg/mL and about
50.0 mg/mL, for example, about 15.0 mg/mL.
According to further embodiments, the anti-bacterial agent to be
employed in the active component of the composition may be selected
from the group of quinolones, including fluoroquinolones, and
suitable derivatives of the same, such as pharmaceutically
acceptable salts, hydrates or solvates thereof. In one embodiment,
fluoroquinolone that may be so employed is moxifloxacin
(chemically,
1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo-[4.3.0]non-8-yl]-6-fluoro-8-met-
hoxy-4-oxo-quinoline-3-carboxylic acid), which is available, e.g.,
under trade name Avelox.RTM. from Bayer Healthcare Corp. of Wayne,
N.J., and under other trade names from other suppliers such as
Alcon Corp. and Bristol-Myers Squibb Co. and has the following
chemical structure:
##STR00003##
A non-limiting example of a possible alternative fluoroquinolone
antibiotic that may be used instead of, or in combination with,
moxifloxacin is gatifloxacin. In some embodiments one or several
glycopeptide antibiotic(s), or a combination of some or all of
them, may be optionally used as a part of the anti-bacterial agent,
in combination with moxifloxacin. One example of such an acceptable
additional glycopeptide antibiotic is vancomycin which can be
introduced into the pharmaceutical composition at a concentration
between about 1 mg/mL and about 100.0 mg/mL, such as between about
5.0 mg/mL and about 50.0 mg/mL, for example, about 10.0 mg/mL.
Vancomycin is available under the trade name Vancocin.RTM. from Eli
Lilly & Co. of Indianapolis, Ind. Other acceptable additional
glycopeptide antibiotics that may be used include teicoplanin,
telavancin, decaplanin, ramoplanin, gentamicin, tobramycin,
amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim.
According to further embodiments, the anti-inflammatory agent to be
employed in the active component of the composition may be selected
from the group of corticosteroids, such as derivatives of
corticosterone, and pharmaceutically acceptable salts, hydrates,
solvates, ethers, esters, acetals and ketals thereof. For example,
a product obtained as a result of a chemically reasonable
substitution of any hydrogen and/or hydroxyl group in the molecule
of corticosterone may be used. In one embodiment, a corticosteroid
that can be so utilized is triamcinolone (chemically, (11.beta.,
16.alpha.)-9-fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione)
having the following chemical formula:
##STR00004##
In another embodiment, a corticosteroid that can be so utilized is
triamcinolone acetonide (chemically,
(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS)-4b-fluoro-6b-glycoloyl-5-hydroxy-4a,6a-
,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphth-
o[2',1':4,5]indeno[1,2-d][1,3]dioxo1-2-one) which is a ketal
derivative of triamcinolone available, e.g., under the trade name
Kenalog.RTM. from Bristol-Myers Squibb Co. of Princeton, N.J., and
under other trade names from other suppliers, and having the
following chemical formula:
##STR00005##
Other corticosteroids, or a combination of some or all of them, may
be used instead of all or a portion of triamcinolone and/or of all
or a portion of triamcinolone acetonide. Some non-limiting examples
of such acceptable other corticosteroids or glucocorticoids include
triamcinolone diacetate, triamcinolone benetonide, triamcinolone
furetonide, triamcinolone hexacetonide, betamethasone acetate,
dexamethasone, fluorometholone and fluocinolone acetonide,
prednisone, prednisolone, methylprednisone, corticol, cortisone,
fluorocortisone, deoxycorticosterone acetate, aldosterone,
budesonide and derivatives, analogs or combinations thereof.
According to other embodiments, pharmaceutical compositions
described herein may further optionally include pharmaceutically
effective quantities of one or several non-steroid
anti-inflammatory drug(s) or NSAID(s). The concentration of
NSAID(s) in the pharmaceutical composition, if used, may be between
about 0.1 mg/mL and about 100.0 mg/mL, such as between about 5.0
mg/mL and about 50.0 mg/mL, for example, about 15.0 mg/mL.
If the pharmaceutical compositions disclosed herein do include
NSAID(s), it is envisioned that some compositions should be free of
the specific NSAID, bromfenac. In other embodiments, however,
bromfenac may be used as well as such NSAID(s) as any of ketorolac,
etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin,
indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen,
flurbiprofen, dexibuprofen, fenoprofen, loxoprofen, oxaprozin,
naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic
acid, meclofenamic acid, flufenamic acid, tolfenamic acid,
meloxicam, piroxicam, ternoxicam, droxicam, lornoxicam, isoxicam,
celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib,
etoricoxib, firocoxib, nimesulide, clonixin, licofelone, and
pharmaceutically acceptable salts, hydrates, solvates, ethers,
esters, acetals and ketals thereof
As mentioned above, the pharmaceutical composition that is the
subject matter of the instant application may further optionally
include one or several pharmaceutically acceptable excipient(s).
Those having ordinary skill in the art will be able to select the
suitable excipient(s). It is worth mentioning that when
moxifloxacin is used in pharmaceutical formulations, it is often
difficult to obtain a stable suspension of another product (e.g., a
corticosteroid such as triamcinolone acetonide) that is present in
the same formulation and that needs to be in a form of a stable
suspension. Without being bound by any particular scientific
theory, such difficulties in obtaining the stable suspension are
believed to be caused by moxifloxacin's tendency to deactivate many
suspending agents resulting in unacceptable coagulation, clumping
and flocculation. As a result, normal delivery through a typical
27-29 gauge cannula is often difficult or even impossible.
Therefore, it is desirable to select an excipient that is stable in
the presence of moxifloxacin and can, therefore, be used as a
solubilizing and suspending agent to ensure that the corticosteroid
such as triamcinolone acetonide safely forms a stable suspension
even when moxifloxacin is also present in the same formulation.
Numerous attempts by others to produce a stable
moxifloxacin/triamcinolone acetonide pharmaceutical composition
suitable for intraocular injection have not been successful.
In some embodiments, an excipient that can be used as a
solubilizing and stabilizing agent to overcome the above-described
difficulties and thus to obtain a stable suspension of the
corticosteroid such as triamcinolone acetonide may be a non-ionic
polyoxyethylene-polyoxypropylene block copolymer having the
following general structure:
HO--(CH.sub.2--CH.sub.2--O).sub.x--(C.sub.3H.sub.6--O).sub.y--(CH.sub.2---
CH.sub.2--O).sub.x--H, wherein x is an integer having the value of
at least 8 and x is an integer having the value of at least 38.
If a non-ionic polyoxyethylene-polyoxypropylene block copolymer is
used as a solubilizing and stabilizing agent in the pharmaceutical
compositions of the instant invention, its contents in the overall
composition may be between about 0.01 mass % and about 10.0 mass %
such as between about 1.0 mass % and about 8 mass %, for example,
about 5.0 mass %.
One non-limiting example of a specific non-ionic
polyoxyethylene-polyoxypropylene block copolymer that can be used
as a solubilizing and stabilizing agent in the pharmaceutical
compositions of the instant invention is the product known under
the trade name Poloxamer 407.RTM. (poly(ethylene
glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol))
available from Sigma-Aldrich Corp. of St. Louis, Mo., with the
molecular weight of the polyoxypropylene portion of about 4,000
Daltons, about a 70% polyoxyethylene content, the overall molecular
weight of between about 9,840 Daltons and about 14,600 Daltons and
having the following chemical structure:
##STR00006##
Non-limiting examples of some other excipients and carriers that
may be used in preparing in the pharmaceutical compositions of the
instant invention include polysorbate (an emulsifier), edetate
calcium disodium (EDTA, a chelating agent), hydrochloric acid (the
pH adjuster) and sterile water.
According to further embodiments, methods for fabricating the
above-described pharmaceutical compositions are provided. A
one-batch formulation method may be used, where the components of
the pharmaceutical formulation can be combined in single container;
the components may be added to the container simultaneously or
consecutively.
In one exemplary, non-limiting procedure, a quantity of an
anti-bacterial agent such as moxifloxacin may be placed into a
mixing container followed by adding a quantity of sterile water and
hydrochloric acid to obtain a slightly acidic mixture (e.g., having
pH of about 6.5) which is stirred until a clear solution is
obtained. In case of moxifloxacin/HCl system, the solution is
stable, allowing the formulation to remain closed system thus
preventing contamination and the loss of sterility.
Next, a quantity of corticosteroid such as micronized triamcinolone
acetonide, a quantity of Poloxamer 407.RTM., a quantity of edetate
calcium disodium and a quantity of polysorbate 80 may be all added
to be combined in the same container with the already prepared
moxifloxacin/HCl solution and stirred together (e.g., by spinning)
for a period of time, e.g., about 6 hours, until a homogenous
suspension has been obtained. The resulting suspension may then be
transferred into single dose vials, capped, sealed, autoclaved and
shaken until cool. Finally, a complete testing for sterility and
the presence of endotoxin may be performed on the product according
to commonly used methods known to those having ordinary skill in
the art.
From the description above, it, therefore, follows that according
to embodiments of the present application, the pharmaceutical
compositions described herein can be formulated as stable two-phase
suspensions as defined above. More specifically, according to these
embodiments, the suspensions at issue consist of two phases, i.e.,
the dispersed phase that is dispersed within the dispersion medium.
The dispersed phase consists of solid particles consisting of a
therapeutically effective quantity of a corticosteroid. No
compounds other that corticosteroids described hereinabove are
present within the solid particles that form the dispersed
phase.
According to such embodiments, the dispersion medium is a liquid
that includes all other compounds that are present in the
pharmaceutical compositions described in the application. The
application envisions no embodiment where corticosteroid can be
used outside the dispersed phase such as in the dispersion medium.
Specifically, the dispersion medium includes the following
components (a)-(e):
(a) at least one anti-bacterial agent of the quinolone group (i.e.,
quinolone, a fluorinated quinolone and derivatives as
described);
(b) at least one solubilizing and suspending agent (i.e., non-ionic
polyoxyethlene-polyoxypropylene block copolymers or
polysorbates);
(c) at least one glycopeptide antibiotic (i.e., vancomycin, or
other antibiotic(s) described hereinabove), the use of this
component in the dispersion medium is optional;
(d) also optionally, at least one non-steroid anti-inflammatory
drug such as bromfenac or other NSAIDs described hereinabove;
and
(e) a carrier.
In one exemplary, non-limiting procedure, the process of preparing
the pharmaceutical compositions described hereinabove may commence
by forming the aqueous dispersion medium. To form the aqueous
dispersion medium, a quantity of an anti-bacterial agent such as
moxifloxacin may be put into a mixing container followed by adding
a quantity of sterile water and hydrochloric acid to obtain a
slightly acidic mixture (e.g., having a pH of about 6.5) which can
be stirred until a clear solution is obtained. In case of
moxifloxacin/HCl system, the solution is stable, allowing the
formulation to remain closed system thus preventing contamination
and the loss of sterility.
After such clear stable solution has been formed, more components
could be added to the solution that is to become the dispersion
medium of the final suspension, i.e., a quantity of Poloxamer
407.RTM. and/or a quantity of polysorbate 80, a quantity of edetate
calcium disodium, optionally a quantity of an antibiotic (e.g.,
vancomycin) and optionally a quantity of an NSAID (e.g., bromfenac)
may be all added to the same container with the already prepared
moxifloxacin/HCl solution.
At the same time, a quantity of corticosteroid such as micronized
triamcinolone acetonide can be added to the above described
solution, followed by stirring everything together (e.g., by
spinning) for a period of time, e.g., about 6 hours, until a
homogenous suspension has been obtained. In that suspension two
phases can be formed: the dispersed phase of the corticosteroid and
the dispersion medium into which the aqueous solution described
above has now been transformed.
Pharmaceutical compositions prepared as described above can be used
to prevent complications that may arise after ophthalmic surgical
operations and procedure. For example, the formulations can be used
during any intraocular surgery, such as cataract surgery, planned
vitrectomy or glaucoma procedures, to prevent or at least
substantially reduce the risk of post-surgery complications, such
as the development of endophthalmitis or cystoid macular edema
(CME), without having the patient use pre- or post-operative
topical ophthalmic drops. Individuals with evidence of
endophthalmitis from prior surgical procedures or traumatic ocular
penetration will benefit from concurrent injection of these
formulations to sterilize infection and reduce damaging
inflammation.
Pharmaceutical formulations described herein can be delivered via
intraocular intravitreal injection which can be transzonular, or,
if desired not transzonular. Intraocular intravitreal injection of
this formulation, whether done via transzonular or via direct pars
plana (trans-scleral) injection, delivers potent broad spectrum
antibiotics directly into the suppurative tissue without requiring
the urgent compounding of multiple individual medications or
multiple individual injections into the eye.
Typically, a pharmaceutical composition described above will be
intraocularly administered to a mammalian subject (e.g., humans,
cats, dogs, other pets, domestic, wild or farm animals) in need of
emergent, urgent or planned ophthalmic surgery treatment. The
effect achieved by such use of pharmaceutical composition described
above may last up to four weeks. The composition is to be injected
intravitreally and trans-zonularly using methods and techniques
known to those having ordinary skilled in the art of ophthalmology.
In some embodiments, the injection can be intraoperative.
Typically, the delivery through a typical 27 gauge cannula can be
employed utilizing a 1 mL TB syringe, with attention to
re-suspending the formulation using momentary flicks and shake just
prior to injection. The medicinal volume (i.e., dosage) required of
this formulation varies based on the type of intraocular procedure,
the degree of postoperative inflammation induced or anticipated,
the risk assessment for postoperative infection, and anatomic
considerations regarding the available volume for the injection
being added to a closed intraocular space.
It is worth mentioning that while intracameral (that is, anterior
chamber) injections are within the scope of the instant invention
such injections instead of posterior chamber (intravitreal)
injection may not be satisfactory in some cases, as the suspension
clogs the trabecular meshwork and aggravates intraocular drainage,
resulting in an intraocular pressure rise postoperative. This is
avoided with intravitreal injection, in addition to retaining the
formulation components into the protein matrix of the vitreous of a
greater duration. Anterior chamber wash out occurs over hours
(antibiotic in solution) and days (steroid in suspension), while
intravitreal injection is retained for weeks.
In alternative embodiments, if desired or necessary the
formulations may also be delivered in the form of eye drops or eye
sprays, as well as via subconjunctival injection, intraocular
intracameral injection, sub-tenon injection, intra-articular
injection or intra-lesional injection, particularly, in, but not
limited to, some cases when necessary to deliver additional
medication when local ocular inflammation and extra-ocular
infection need suppression. Intravitreal delivery of steroid has
historically been used to treat clinically significant cystoid
macular edema (CME); the application of this formulation into the
vitreous during routine intraocular procedures brings more
aggressive prophylaxis against CME occurrence. Additionally, the
suspension of this formulation is useful for staining vitreous
during planned and unplanned vitrectomies, improving visualization
of this otherwise transparent intraocular tissue, improving
vitrectomy outcomes and reducing complications resulting from
inadequate or tractional vitreous removal. In still further
embodiments, there is also envisioned intra-canalicular delivery,
i.e., delivery via a lacrimal canaliculus implant.
In some further alternative embodiments, instead of delivering the
above-described compositions comprising both anti-bacterial and
anti-inflammatory agents, consecutive injections may be used
instead, if desired. For example, triamcinolone or prednisolone may
be injected first, immediately followed by the injection of
moxifloxacin or vice versa.
In still further embodiments, the pharmaceutical compositions
described hereinabove may be incorporated into a lens, such as an
intraocular lens or a contact lens. The lens can be made of a
hydrophobic or a hydrophilic material, as desired. One non-limiting
example of such a material may be poly(2-hydroxyethyl methacrylate)
(HEMA). The lens made of other materials may be also selected by
those having ordinary skill in the art. The pharmaceutical
compositions may be incorporated into a lens, such as an
intraocular lens before the IOL is implanted in a surgical
procedure such as a cataract surgery or a surgery that is performed
to correct myopia. To illustrate, a pharmaceutical composition to
be used for these purposes may include any corticosteroid and any
anti-bacterial agent described above, to be selected by a skilled
practitioner.
To further exemplify but not to unduly limit, a composition to be
incorporated into the lens such as the IOL may include a
corticosteroid such as triamcinolone, prednisone, prednisolone or
dexamethasone and an anti-bacterial agent, e.g., moxifloxacin or
gatifloxacin. Further components of a pharmaceutical composition to
be incorporated into the IOL optionally include solubilizing and
suspending agent such as Poloxamer 407.RTM. and also optionally an
additional antibiotic such as vancomycin, as described above.
To incorporate a pharmaceutical composition into the IOL, a variety
of methods may be employed. In one exemplary non-limiting
embodiment, the IOL may be immersed, under ambient conditions, into
a solution of a selected pharmaceutical composition that is to be
incorporated into the IOL. Without being bound by any particular
scientific theory, it appears the process of incorporation can
occur by adsorption. The time necessary to have the IOL adsorb the
required quantity of the solution may be between about 6 hrs and 48
hours, for example, between about 12 hrs and about 36 hrs, such as
about 24 hrs, followed by optional additional immersion of the IOL
(now having the pharmaceutical composition ensconced into the IOL)
into a saline solution for additional period of time of about 24
hrs, if desired.
It will be understood by those having ordinary skill in the art
that the specific dose level and frequency of dosage for any
particular patient may be varied and will depend upon a variety of
factors including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
age, body weight, general health, gender, diet, and the severity of
the particular ophthalmological condition being treated.
In additional embodiments, pharmaceutical kits are provided. The
kit includes a sealed container approved for the storage of
pharmaceutical compositions, the container containing one of the
above-described pharmaceutical compositions. An instruction for the
use of the composition and the information about the composition
are to be included in the kit.
The following examples are provided to further elucidate the
advantages and features of the present invention, but are not
intended to limit the scope of the invention. The examples are for
the illustrative purposes only. USP pharmaceutical grade products
were used in preparing the formulations described below.
C. Examples
EXAMPLE 1
Preparing a Pharmaceutical Composition
A pharmaceutical composition was prepared as described below. The
following products were used in the amounts and concentrations
specified:
(a) about 1.5 g of triamcinolone acetonide, at a concentration of
about 15.0 mg/mL;
(b) about 0.1 g of moxifloxacin hydrochloride, at a concentration
of about 1.0 mg/mL;
(c) about 1 mL of polysorbate 80, at a concentration of about 1.0
mass %;
(d) about 0.2 g of edetate calcium disodium, at a concentration of
about 0.2 mass %;
(e) about 1 g of Poloxamer 407.RTM., at a concentration of about
1.0 mass %;
(f) hydrochloric acid, to adjust pH to about 6.5; and
(g) about 100.0 mL of sterile water for injection.
Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker
with a spin bar. Sterile water for injection was added to about 1/3
of the volume of the beaker. While spinning, moxifloxacin was
dissolved by adding hydrochloric acid until a clear solution having
the final pH of about 6.5 was obtained.
The solution was combined with micronized triamcinolone acetonide,
Poloxamer 407.RTM., edetate calcium disodium and polysorbate 80 and
allowed to spin for about 6 hours until a hydrated and homogenous
suspension was obtained.
The suspension was transferred into de-pyrogenated, single dose
vials (2 mL size), capped and sealed, followed by autoclaving and
shaking the vials until cool. Complete sterility and endotoxin
testing was performed by an outside laboratory to ensure
safety.
The formulation prepared as described above was tested for the
particle sizes and their distribution. The results showed that very
fine particles were obtained and the size distribution was quite
uniform. Specifically, about 99% of all the particles had the
diameter of 5 .mu.M or less, where the sizes within the range
between about 1 .mu.M and 4 .mu.M dominated and constituted about
82% of all particles. Just 0.1 to 0.2% of all the particles were
large than about 10 .mu.M in diameter.
The formulation prepared as described above was also tested for
stability after 6 months of storage. After this period of storage
no loss of potency was observed (as measured by HPLC); the
formulation was visually stable at room temperature and readily
re-suspended with gentle shaking with no increase of particle size
or flocculation.
EXAMPLE 2
Preparing a Pharmaceutical Composition Containing Vancomycin
A pharmaceutical composition was prepared as described in Example
1, supra. The composition was autoclaved and sonicated for about 60
minutes and about 96 mL of the composition were combined with about
4 mL of vancomycin at a concentration of about 250 mg/mL. The pH of
the mixture was adjusted to about 6.0-6.5 using hydrochloric acid.
The product was then transferred into vials (at about 1 mL plus 5
drops per vial) and frozen. The product has kept its stability and
potency for at least six months.
EXAMPLE 3
Using a Pharmaceutical Composition
A pharmaceutical composition fabricated as described in Example 1,
supra, was administered to about 1,600 patients. To each, it was
introduced using intravitreal transzonular injection. The injection
was intraoperative. Only a very few patients, at the rate of about
only 1 in 4,000, have developed any infection or suffered from
other side effects that required further treatment, which is a
substantial improvement over a typical rate of about 8% for the
patients that did not receive the injection.
EXAMPLE 4
Incorporating a Pharmaceutical Composition into an IOL
A pharmaceutical composition was prepared as described in Example
2, supra. An IOL made of HEMA having about 26% water content was
immersed into the composition for about 24 hours. The lens was a
posterior chamber mono focal IOL known in the industry as SOFTEC
HD.
After the 24 hr long immersion in the pharmaceutical composition,
the lens was than immersed into a standard saline solution for
additional 24 hours resulting in clear lens that was ready for
installation.
EXAMPLE 5
Preparing a Pharmaceutical Composition Containing NSAID
Bromfenac
A pharmaceutical composition was prepared as described below. The
following products were used in the amounts specified:
(a) about 10.0 g of micronized prednisolone acetate;
(b) about 5.454 g of moxifloxacin hydrochloride monohydrate;
(c) about 1.035 g of bromfenac sodium powder;
(d) about 10.0 mL of an aqueous solution of polysorbate 80, at a
concentration of about 1.0 mass %;
(e) about 4.0 g of boric acid powder;
(f) about 14.0 g of Poloxamer 407.RTM.;
(g) about 3.17 g of sodium chloride granules;
(h) 20% solution of sodium hydroxide, to adjust pH; and
(i) about 1.0 L of sterile water for injection.
Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker
with a spin bar. Sterile water for injection was added, about 60%
of the total volume of water. While spinning, moxifloxacin was
dissolved by adding sodium hydroxide to adjust the pH to about 7.4
to 7.8, followed by additional stirring for about 5 minutes, until
a clear solution was obtained. Bromfenac was then added, with
continued stirring, until completely dissolved which is indicated
by the solution being visibly clear. The pH then was adjusted again
to maintain it in the range of 7.4 to 7.8.
The solution was combined with polysorbate 80, Poloxamer 407 and
boric acid, with continued stirring, followed by slowly adding
micronized prednisolone acetate, the remainder of water, with
continued spinning for about 20 minutes, until a hydrated and
homogenous product was obtained.
The product was then transferred into pre-sterilized
de-pyrogenated, 100 mL vials, capped and sealed, followed by
autoclaving (about 121.degree. C. and about 15.0 psi of pressure
for about 30 minutes) shaking and sonicating the vials for about 30
minutes.
The composition obtained as described in this Example can then be
incorporated into an IOL as described in Example 4, supra.
Although the invention has been described with reference to the
above examples, it will be understood that modifications and
variations are encompassed within the spirit and scope of the
invention. Accordingly, the invention is limited only by the
following claims.
* * * * *